A Domino 10-Step Total Synthesis of FR252921 and Its Analogues, Complex Macrocyclic Immunosuppressants

Overview

Journal J Am Chem Soc

Publisher American Chemical Society

Specialty Chemistry

Date 2019 Aug 23

PMID 31436963

Citations 7

Authors

Yong Chen

Guilhem Coussanes

Caroline Souris

Paul Aillard

Dainis Kaldre

Kathrin Runggatscher

Stefan Kubicek

Giovanni Di Mauro

Boris Maryasin

Nuno Maulide

Affiliations

Soon will be listed here.

Abstract

FR252921, FR252922, and FR256523 are a family of potent macrocyclic polyene immunosuppressive agents with a novel mode of action. However, the lack of an efficient and flexible synthesis has hindered further biological studies, mostly due to the fact that the natural products appear to be kinetic isomers regarding the triene moiety. Herein, we report the development and application of an unprecedented, unique domino Suzuki-Miyaura/4π-electrocyclic ring-opening macrocyclization, resulting in a concise, unified, and stereoselective synthetic route to these complex targets in only 10 steps. This in turn enables ready access to a range of unnatural analogues, among which several compounds showed inhibition of T-lymphocyte proliferation at levels equal or superior to those of the natural products themselves.

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